Composition to help stop smoking

ABSTRACT

A composition for administration to the nasal mucosa of a subject comprises a solution of nicotine or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable solvent. The composition has a nicotine concentration in the range of about 10 to about 40 mg/ml and contains a suitable agent to produce a viscosity in the range of about 1 to about 30 centipoise. The composition assists in reduction of the desire of the subject to smoke tobacco or provides a substitute for tobacco smoking.

This application is a 371 of PCT/CA93/00003 filed Jan. 4, 1993.

This invention relates to compositions and methods useful for subjectswho wish to reduce tobacco smoking or to find a socially acceptablesubstitute.

BACKGROUND OF THE INVENTION

Because of the reported harmful effects of tobacco smoking and also dueto the current social attitudes to smoking, resulting in ever-increasingsmoke-free public areas, there is great pressure on tobacco smokers tostop smoking or to find a more socially acceptable alternative.

For those who are unable to give up smoking completely, various forms ofnicotine-replacement therapy have been suggested.

Nicotine-containing chewing gum is available commercially and hasprovided a satisfactory substitute for tobacco-smoking for some people.For many people, nicotine gum does not alleviate the craving fortobacco, due to the gradually achieved and low blood nicotine levelsproduced. Many people also experience unpleasant side effects, such asnausea and indigestion (Jarvis et al., British Medical Journal, Vol.285, p. 537 (1982); Schneider, Comprehensive Therapy, Vol. 13, p. 32(1987)).

Nicotine-containing nose drops have been reported (Russel et al.,British Medical Journal, Vol. 286, p. 683 (1983); Jarvis et al., Brit.J. of Addiction, Vol. 82, p. 983 (1987)). Nose drops, however, aredifficult to administer and are not convenient for use at work or inother public situations. There may also be local nasal irritation withuse of nicotine nose drops. The difficulty in administration alsoresults in unpredictability of the dose of nicotine administered.

The use of skin patches for transdermal administration of nicotine hasbeen reported (Rose, in Pharmacologic Treatment of Tobacco Dependence,(1986) pp. 158-166, Harvard Univ. Press). Nicotine-containing skinpatches can cause local irritation and the absorption of nicotine isslow and affected by cutaneous blood flow.

U.S. Pat. Nos. 4,920,989 and 4,953,572 disclose the use of an inhalednicotine aerosol, sometimes in conjunction with nicotine skin patches,as a means of reducing tobacco smoking. When skin patches were used,transdermal absorption of nicotine gave blood nicotine levels comparableto those achieved by tobacco smoking. The use of the nicotine aerosolalone delivered substantially less nicotine to the blood than is seenwhile smoking tobacco but did provide sensations of irritation in theairways of the user, thus mimicking sensations associated with tobaccosmoking.

In order to ensure that the droplets of nicotine solution would becarried into the respiratory airways on inhalation through the mouth inimitation of smoking, rather than being deposited in the oral cavity,the aerosol droplet size employed was 10 microns or less.

Although a certain degree of airway irritation is desired to mimicsmoking, this cannot be readily controlled and the irritation may bepronounced, making the use of a nicotine aerosol undesirable.

Perkins et al. (Behavior, Research Methods, Instruments and Computers(1986), vol. 18, p.420 and Psychopharm. (1989), vol. 97, p. 529)reported use of a nicotine aerosol spray as a means of administeringnicotine to a test subject in controllable amounts in order to study thephysiological effects of nicotine. Under their test conditions, theywere able to employ a dilute solution of nicotine administered inseveral doses to deliver 1.8 ml. over a 5 minute period to restingsubjects and did not investigate a practical nicotine preparation foreveryday use, such as is required for anti-smoking treatment or as asubstitute for tobacco smoking.

U.S. Pat. No. 4,579,858 discloses a nicotine-containing preparation ofhigh viscosity which is administered to the nose as a viscous plug. Thesurface area of such a plug which is in contact with the nasal mucosa islimited and this is reflected in the relatively low blood nicotinelevels achieved by this method of nicotine administration.

There remains a need for a nicotine preparation suitable as a substitutefor tobacco smoking, which can be conveniently used in public, as thesubject goes about his or her normal activities over an extended periodof time.

SUMMARY OF INVENTION

A composition for nasal administration is provided to assist inreduction of the desire of a subject to smoke tobacco or to provide asubstitute for tobacco smoking, the composition comprising a solution ofnicotine or a pharmaceutically acceptable salt thereof in apharmaceutically acceptable solvent, the composition having a pH in therange of about 5 to about 6.5, a nicotine concentration in the range ofabout 10 to about 40 mg/ml and containing a suitable agent to produce aviscosity in the range of about 1 to about 99 centipoise.

SUMMARY OF THE DRAWINGS

The invention, as exemplified by preferred embodiments, is describedwith reference to the drawings in which:

FIGURE 1 shows the blood nicotine level of a subject at various timeintervals after administration of the nicotine-containing composition ofthe invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a convenient, inexpensive and effectivealternative to tobacco smoking, by administration of an effective doseof nicotine by nasal spray to a subject.

Nicotine-containing compositions and nasal sprays suitable for nasaladministration are also provided.

The smoking alternative provided by the present invention may be used toassist those attempting to stop tobacco smoking or may be usedindefinitely as a substitute for tobacco smoking which avoids both theundesired side effects of tobacco smoking on other people in thevicinity of the smoker and also the deleterious effects on the smoker ofother substances such as carcinogens and carbon monoxide in tobaccosmoke. The nicotine-containing compositions and sprays of the inventionmay be used without interference with the user's productive work orother normal activities.

When a nicotine-containing solution is applied to the nasal mucosa,nicotine can be absorbed directly into the bloodstream. If a smokingsubstitute is to be provided by this means, sufficient nicotine must beapplied and absorbed to give a rapid increase in blood nicotinecomparable to that achieved by tobacco smoking if the craving to smokeis to be eliminated. Previously available smoking substitutes often failin this regard due to a too small or too delayed increase in bloodnicotine level.

It is desirable that nasal administration of nicotine provides asufficient dose of nicotine to a sufficiently large area of the nasalmucosa to give the desired rapid increase in blood nicotine levelwithout providing a local nicotine concentration so high that it causesmucosal irritation and without requiring the delivery of such a largevolume of nicotine-containing composition that a portion of theadministered dose runs from the nose, causing annoyance andinconvenience to the user.

In accordance with the present invention, nicotine or a pharmaceuticallyacceptable nicotine salt is dissolved in a pharmaceutically acceptablesolvent, such as phosphate-buffered saline, and is adjusted to a pH inthe range of about 5 to about 6.5, for optimal absorption through thenasal mucosa. A pH of about 5.8 is preferred.

Pharmaceutically acceptable nicotine salts are known to those skilled inthe art and include nicotine tartrate and nicotine hydrogen tartrate.

Other suitable pharmaceutically acceptable buffering agents will beknown to those skilled in the art.

In order to improve retention of the nicotine-containing composition ofthe invention in the nose, a suitable agent is added to produce aviscosity in the range of about 1 to about 99 centipoise. A viscosity inthe range of about 10 to about 20 centipoise is preferred.

As will be known to those skilled in the art, a variety of agents may beused to produce the desired viscosity, including cellulose, substitutedcelluloses such as carboxymethyl cellulose and methyl cellulose, gumarabic and polyethylene glycol. The desired viscosity may also beproduced by use of an oil emulsion, the oil phase being any suitablenasally-acceptable oil including, for example, lanolin or beeswax. Anyviscosity producing agent used must, of course, be pharmaceuticallyacceptable and well tolerated by the nasal mucosa.

The nicotine-containing composition of the present invention is appliedto the nose as a spray of droplet size selected to favour deposition ofthe droplets in the nose and minimise inhalation of the nicotinecomposition into the airways beyond the nose.

Studies by Yu et al (J. Pharmaceut. Sci., Vol. 73, p. 344 (1984)) haveshown that droplet size of a spray delivered into the nose or inhaledthrough the mouth influences the location of droplet deposition. Theseauthors showed that, during inhalation, droplets of 2 to 6 micronslargely reach the terminal bronchi and alveoli, whereas a majority ofdroplets greater than 10 microns is required to localise delivery in thenose.

The nicotine-containing composition of the invention may be applied tothe nose by any suitable atomiser or spray device which produces a sprayof droplet size greater than about 10 microns. For example, conventionalventuri-type atomisers such as are used for nasal decongestants ormetered dose spray devices such as are used for nasal steroidapplication may be employed. These devices produce 98% of dropletsgreater than 16 microns and a majority of droplets of approximately 100to 200 microns. As will be understood by those skilled in the art, theviscosity of the composition of the invention should be optimised forthe type of spray device employed. For example, it has been found by theinventors that when a venturi-type atomiser is used, the nicotinecomposition should have a viscosity of not more than about 10centipoise. When a metered dose spray device is used, a composition ofviscosity up to about 30 centipoise may be used with good dropletproduction, with increasing viscosities above that tending to produce astream of liquid rather than an aerosol. A suitable compositionviscosity for a particular type of spray device may be readilydetermined by those skilled in the art.

When then nasal spray of the invention is used, nicotine is not drawninto the user's airways beyond the nose, thus avoiding respiratoryirritation and allowing the use of higher nicotine concentrations,permitting blood nicotine levels to be boosted to those comparable withsmoking without concomitant irritation.

As will be understood by those skilled in the art, the nicotineconcentration in the composition of the invention and the volume ofcomposition delivered to the nose may be varied to provide a desirednicotine dose to a subject. The volume delivered should be selected toas to be well retained in the nose, without running out. The nicotineconcentration should not be so high as to produce unacceptable localirritation when sprayed in the required amount.

The inventors have found that the composition of the invention can beapplied in a volume of about 0.03 to about 0.08 ml. per nostril withgood retention of the composition in the nose. A nicotine concentrationin the range of about 10 to about 40 mg/ml is well tolerated by thenasal mucosa when applied in accordance with the present invention.

In order to approximate the dose of nicotine delivered to the blood bysmoking one cigarette, is, approximately 1 mg (Russell et al., above),about 2 mg nicotine should be delivered to the nose. If, for example, anatomiser delivering about 0.03 ml. nicotine composition per squeeze isemployed, and the composition has a concentration of 20 mg/ml nicotine,one squeeze delivers 0.06 mg nicotine and three applications willdeliver approximately 2 mg nicotine.

In accordance with a preferred embodiment of the invention, acomposition having a viscosity of about 10 centipoise and nicotineconcentration about 20 mg/ml, dissolved in phosphate buffered saline ata pH of about 5.8 is employed. The composition is delivered to the noseby a spray device which delivers about 0.03 ml. of the composition peractivation of the device in the form of a spray having droplets of atleast 10 microns diameter.

The nicotine composition of the invention may also optionally containone or more of a flavouring agent such as menthol, and a preservingagent such as benzoic acid or an antioxidant such as ascorbic acid.Suitable flavourings and preservatives acceptable in foods andpharmaceuticals will be known to those skilled in the art, as willsuitable concentrations of these agents.

Use of nicotine-containing compositions of the invention applied as anasal spray in accordance with the invention has been found to be welltolerated by human subjects, with minimal side effects in the form of amild and temporary runny nose.

Use of the nicotine-containing nasal spray of the invention has beenfound to permit a smoker to function efficiently in a non-smoking workenvironment for at least three years without withdrawal symptoms ortobacco cravings.

The following examples are merely illustrative of the invention and theinvention is not necessarily limited thereto.

EXAMPLE 1

Nicotine (98-100% free base, catalogue #3876, Sigma Chemical Co., StLouis, Mo.) was dissolved in phosphate buffered saline (PES: 0.175 g Na₂HPO₄ /100 ml; 1.21 g NaH₃ PO₄ /100 ml; 0.292 g NaCl/100 ml) to give anicotine concentration of 20 mg/ml. This solution has a pH of 5.8 and anosmolarity of 290 mosm. Carboxymethyl-cellulose was added to give aviscosity of 5 centipoise. The solution was sterilised by passing itthrough a 0.2 micron filter and 10 ml of the sterilised solution wasplaced in a conventional venturi-type atomiser.

The atomiser was used to administer 2.4 mg nicotine to the nose of ahuman subject over about 5 seconds, by four squeezes of the atomiser(two squeezes into each nostril). Blood samples were collected from ananticubital vein in the arm of the subject at various time intervalsafter nicotine administration (time zero in FIGURE 1) and blood nicotineconcentrations were determined by the method of Feyerabend and Russell(J. Pharm. Pharmacol., Vol. 32, pp. 178-181 (1980)). Results are shownin FIGURE 1.

The concentrations of blood nicotine achieved were similar to thoseresulting from smoking of a cigarette and the peak value occurred around15 minutes from administration, only slightly later than after cigarettesmoking.

Although only preferred embodiments of the invention have been describedand illustrated, the present invention is not limited to the features ofthese embodiments, but includes all variations and modifications withinthe scope of the claims.

I claim:
 1. A nicotine-containing spray for administration to the nasalmucosa of a subject to assist in reduction of the desire of the subjectto smoke tobacco or to provide a substitute for tobacco smoking, thespray being in the form of droplets of a size in the range of from about10 to about 200 microns and comprising a solution of nicotine or apharmaceutically acceptable salt thereof in a pharmaceuticallyacceptable solvent, the spray having a nicotine concentration in therange of about 10 to about 40 mg/ml and further comprising a viscosityagent providing the spray with a viscosity in the range of about 1 toabout 30 centipoise.
 2. A spray in accordance with claim 1 wherein thepharmaceutically acceptable solvent is phosphate buffered saline.
 3. Aspray in accordance with claim 1 wherein the viscosity agent iscellulose or a substituted cellulose.
 4. A spray in accordance withclaim 1 wherein the viscosity agent is carboxymethyl cellulose.
 5. Aspray in accordance with claim 1 wherein the viscosity agent is apharmaceutically acceptable oil emulsion.
 6. A spray in accordance withclaim 1 wherein the pH is in the range of about 5 to about 6.5
 7. Aspray in accordance with claim 1 wherein the pH is about 5.8 and thenicotine concentration is about 20 mg/ml, and wherein the spray containscarboxymethyl cellulose to provide the spray with a viscosity of about 5to about 20 centipoise.
 8. A nicotine containing spray in accordancewith claim 1, wherein the droplets are about 100 to about 200 microns indiameter.
 9. A spray in accordance with claim 1, wherein the spray isdelivered from a spray device for delivering an effective dose of thespray to the nose.
 10. A spray in accordance with claim 1, furthercomprising one or more agents selected from the group consisting of aflavouring agent, a preserving agent and an antioxidant.
 11. A method ofassisting in the reduction of the desire of a subject to smoke tobacco,comprising administering an effective dose of a nicotine-containingspray in accordance with any one of claims 2 to 5, 6 or 8 to the nasalmucosa of the subject.
 12. A method of assisting in the reduction of thedesire of a subject to smoke tobacco, comprising administering aneffective dose of a nicotine-containing spray in accordance with claim 8to the nasal mucosa of the subject.
 13. A method of assisting in thereduction of the desire of a subject to smoke tobacco, comprisingadministering a nicotine-containing spray in accordance with claim 7 tothe nasal mucosa of the subject.
 14. A method of providing to a smoker asubstitute for tobacco smoking, comprising administering an effectivedose of a nicotine-containing spray in accordance with any one of claims2 to 5, 6 or 7 to the nasal mucosa of the subject.
 15. A method ofproviding to a smoker a substitute for tobacco smoking, comprisingadministering an effective dose of a nicotine-containing spray inaccordance with claim 8 to the nasal mucosa of the subject.
 16. A methodof providing to a smoker a substitute for tobacco smoking, comprisingadministering a nicotine-containing spray in accordance with claim 7 tothe nasal mucosa of the subject.
 17. A method of assisting in thereduction of the desire of a subject to smoke tobacco, comprisingadministering an effective dose of a nicotine-containing spray inaccordance with claim
 1. 18. A method of assisting in the reduction ofthe desire of a subject to smoke tobacco, comprising administering anicotine-containing spray in accordance with claim 1 to the nasal mucosaof the subject in an amount which delivers a nicotine dose in the rangeof about 1 to about 3 mg.
 19. A method of providing to a smoker asubstitute for tobacco smoking, comprising administering an effectivedose of a nicotine-containing spray according to claim 1 to the nasalmucosa of the subject.
 20. A method of providing to a smoker asubstitute for tobacco smoking, comprising administering anicotine-containing spray in accordance with claim 1 to the nasal mucosaof the subject in an amount which delivers a nicotine dose in the rangeof about 1 to about 3 mg.
 21. A method according to claim 17, whereinthe nicotine-containing spray is administered in a volume of about 0.03to about 0.08 ml.
 22. A method according to claim 19, wherein thenicotine-containing spray is administered in a volume of about 0.03 toabout 0.08 ml.